Intern Emerg Med DOI 10.1007/s11739-013-1042-7
CE - LETTER TO THE EDITOR
Laboratory tests during direct oral anticoagulant treatment Sophie Testa • Oriana Paoletti
Received: 30 October 2013 / Accepted: 26 December 2013 Ó SIMI 2014
Dear Sir, We read with great interest the recently published pro(s) and con(s) debate on ‘‘Laboratory tests during direct oral anticoagulant treatment’’, by Pengo and Di Minno et al. [1, 2]. The discussed topic has great importance in daily clinical practice because direct oral anticoagulant agents (DOAC) have been recently approved for the treatment of venous thromboembolism and for stroke prevention in atrial fibrillation. DOAC belong to different classes of oral anticoagulants: dabigatran is an anti-IIa selective inhibitor, while rivaroxaban, apixaban and edoxaban are selective anti-Xa inhibitors. Even if they show a similar pharmacological profile, their pharmacokinetic (PK) and pharmacodynamic (PD) characteristics are different (Table 1). As Di Minno et al. [2] discuss, DOAC have predictable PK/PD in standard conditions, overcoming limitations of vitamin K antagonists, due to the relatively wide therapeutic window, the shorter half-life and the rapid onset of action. For these characteristics, DOAC have been evaluated and approved for fixed-dose administration, without routine laboratory monitoring. Phase III clinical trials, performed on selected populations through exclusion and inclusion criteria, show good results without laboratory monitoring, thus the ‘‘no laboratory testing need’’ has been translated into daily clinical practice. As a consequence, in standard clinical conditions,
S. Testa (&) O. Paoletti Laboratory of Clinical Pathology and Microbiology, Haemostasis and Thrombosis Center, AO Istituti Ospitalieri, Cremona, Italy e-mail: [email protected]
laboratory monitoring is not necessary, except for emergency conditions that we will discuss below. However, to approach the real world, we should consider three main points: 1.
2.
3.
These drugs demonstrate high intra-inter variability in their plasma concentrations at a steady state, independently of the type of DOAC and patient characteristics, such as gender, age, renal function and body weight [3]. Pharmacokinetic and pharmacodynamic profiles change significantly in relation to renal/liver impairment, and in the real world, renal impairment affects nearly 30 % of atrial fibrillation patients, and is associated with an increased risk of major complications [3]. All DOAC are substrates of P-gp, and only anti-Xa inhibitors are metabolized through CY [1]. Many drugs interact with P-gp and CY and, as a consequence, DOAC plasma activity should be increased or reduced in comparison to standard metabolism. Since the effect of both metabolic impairments and multiple drug interactions is still unknown, a control of anticoagulant activity might be recommended.
Taking into account these considerations, even assuming based on phase III clinical studies that laboratory monitoring is not necessary in ‘‘patients in standard conditions’’, the same approach could not be safe in patients with different clinical problems, such as renal/liver disease, possible interaction with other drugs, elderly, under/over weight, assessment of compliance, risk for over/under anticoagulation. All these clinical conditions might require an elective laboratory control [4]. Different are the emergency clinical conditions, such as patients presenting in the emergency department with
123
Intern Emerg Med Table 1 AVK, aIIa and aXa oral anticoagulants: main pharmacokinetic and pharmacodynamic characteristics Characteristics
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Bioavailability (%)
98
6–7
63–79
66
50
Tmax (h)
72–120
2–3
2–4
1–3
2–3
Half-life (h)
20–60
7–17
7–13
8–15
9–11
Protein binding
99
35
95
87
54
Food effect
Yes
Delayed absorption
Delayed absorption
No
No
Metabolism/elimination
100 % liver
80 % renal
35 % renal
27 % renal
35 % renal
Substrate CYp
Yes
No
Yes
Yes
Yes
Substrate P-gp
No
Yes
Yes
Yes
Yes
Food interaction
Yes
No
No
No
No
Target
II, VII, IX, X, PC
aIIa
aXa
aXa
aXa
adverse events (thrombosis, bleeding), with the need of an immediate reverse of anticoagulation or for perioperative management, in which the control of anticoagulation is mandatory for safe surgery or invasive procedures [4, 5]. To this aim, the Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis very recently stated that monitoring is necessary in the clinical conditions previously reported. DOAC interfere with many coagulation tests and the aim is to find a test with both good linearity at increasing drug concentrations and good sensitivity for measuring therapeutic and over/sub-therapeutic levels. Many studies have been published in the past 3 years showing sensitivity and specificity of different coagulation tests for each molecule, with different reagents. Specific tests, such as diluted thrombin time (dTT), ecarin clotting time (ECT) and chromogenic ecarin test (ECA) for dabigatran and modified chromogenic anti-Xa assays for anti-Xa inhibitors, have shown the best linearity and sensitivity. DOAC anticoagulant activity should be expressed in drug concentration (ng/ml) [4]. The clinical relevance of plasma drug concentrations in relation to bleeding/thrombotic complications was underlined in the FDA report on the RE-LY study in which dabigatran trough plasma concentrations \50 ng/ml were significantly associated with the risk of stroke, while increased plasma levels were associated with increased bleeding risk. From this analysis, we can derive two considerations: (1) DOAC plasma concentration is associated with thrombotic and haemorrhagic risks; (2) the trough concentration (Ctrough) seems to be preferred to the peak concentration (Cmax) at a steady state. Finally, the measurement of the anticoagulant level is crucial for patients undergoing both elective end emergency surgery or invasive procedures, in which the simple evaluation of DOAC half-life may not be safe in the real world patient population. The RE-LY study shows that among patients undergoing elective surgery a 3.8 % rate of
123
major bleeding complications, while in emergency surgery, bleeding complications are 17.8 %. As we do for patients on vitamin K antagonists, in which the accepted cut-off for surgery/invasive procedures is a PT INR value B1.5, also for DOAC we need to know residual concentration levels and an ‘‘interventional cut-off level’’. This type of approach has been recently proposed as a consensus guideline in which dabigatran and rivaroxaban concentrations B30 ng/ml were considered the critical cut-off for allowing surgery in patients at high risk of bleeding [5]. This methodology also has great relevance to know when the normalization of DOAC anticoagulant effect is necessary, especially in case of major bleeding or emergency surgery [5]. For all these reasons, we believe that laboratory testing represents a valid mean to empower safety and efficacy of DOAC treatment. Although DOAC specific tests are not available in all clinical laboratories, in our opinion this should not be a valid reason to deny the clinical importance of anticoagulant activity measurement of these new drugs. Nevertheless, phase IV clinical trials are required to validate DOAC management. Conflict of interest
None.
References 1. Pengo V (2013) Laboratory tests during direct oral anticoagulant treatment? Yes. Intern Emerg Med 8:371–372 2. Di Minno G, Ricciardi E, Scalera A (2013) Laboratory tests during direct oral anticoagulant treatment? No. Intern Emerg Med 8:367–370 3. Gong IY, Richard BK (2013) Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 29(7):S24– S33 4. Tripodi A, Di Iorio G, Lippi G, Testa S, Manotti C (2012) Position paper on laboratory testing for patients taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and CISMEL. Clin Chem Lab Med 12:2137–2140
Intern Emerg Med 5. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sie P (2013) Management of major bleeding complications and emergency
surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP). Ann Fr Anesth Reanim 10:691–700
123
CE - LETTER TO THE EDITOR
Laboratory tests during direct oral anticoagulant treatment Sophie Testa • Oriana Paoletti
Received: 30 October 2013 / Accepted: 26 December 2013 Ó SIMI 2014
Dear Sir, We read with great interest the recently published pro(s) and con(s) debate on ‘‘Laboratory tests during direct oral anticoagulant treatment’’, by Pengo and Di Minno et al. [1, 2]. The discussed topic has great importance in daily clinical practice because direct oral anticoagulant agents (DOAC) have been recently approved for the treatment of venous thromboembolism and for stroke prevention in atrial fibrillation. DOAC belong to different classes of oral anticoagulants: dabigatran is an anti-IIa selective inhibitor, while rivaroxaban, apixaban and edoxaban are selective anti-Xa inhibitors. Even if they show a similar pharmacological profile, their pharmacokinetic (PK) and pharmacodynamic (PD) characteristics are different (Table 1). As Di Minno et al. [2] discuss, DOAC have predictable PK/PD in standard conditions, overcoming limitations of vitamin K antagonists, due to the relatively wide therapeutic window, the shorter half-life and the rapid onset of action. For these characteristics, DOAC have been evaluated and approved for fixed-dose administration, without routine laboratory monitoring. Phase III clinical trials, performed on selected populations through exclusion and inclusion criteria, show good results without laboratory monitoring, thus the ‘‘no laboratory testing need’’ has been translated into daily clinical practice. As a consequence, in standard clinical conditions,
S. Testa (&) O. Paoletti Laboratory of Clinical Pathology and Microbiology, Haemostasis and Thrombosis Center, AO Istituti Ospitalieri, Cremona, Italy e-mail: [email protected]
laboratory monitoring is not necessary, except for emergency conditions that we will discuss below. However, to approach the real world, we should consider three main points: 1.
2.
3.
These drugs demonstrate high intra-inter variability in their plasma concentrations at a steady state, independently of the type of DOAC and patient characteristics, such as gender, age, renal function and body weight [3]. Pharmacokinetic and pharmacodynamic profiles change significantly in relation to renal/liver impairment, and in the real world, renal impairment affects nearly 30 % of atrial fibrillation patients, and is associated with an increased risk of major complications [3]. All DOAC are substrates of P-gp, and only anti-Xa inhibitors are metabolized through CY [1]. Many drugs interact with P-gp and CY and, as a consequence, DOAC plasma activity should be increased or reduced in comparison to standard metabolism. Since the effect of both metabolic impairments and multiple drug interactions is still unknown, a control of anticoagulant activity might be recommended.
Taking into account these considerations, even assuming based on phase III clinical studies that laboratory monitoring is not necessary in ‘‘patients in standard conditions’’, the same approach could not be safe in patients with different clinical problems, such as renal/liver disease, possible interaction with other drugs, elderly, under/over weight, assessment of compliance, risk for over/under anticoagulation. All these clinical conditions might require an elective laboratory control [4]. Different are the emergency clinical conditions, such as patients presenting in the emergency department with
123
Intern Emerg Med Table 1 AVK, aIIa and aXa oral anticoagulants: main pharmacokinetic and pharmacodynamic characteristics Characteristics
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Bioavailability (%)
98
6–7
63–79
66
50
Tmax (h)
72–120
2–3
2–4
1–3
2–3
Half-life (h)
20–60
7–17
7–13
8–15
9–11
Protein binding
99
35
95
87
54
Food effect
Yes
Delayed absorption
Delayed absorption
No
No
Metabolism/elimination
100 % liver
80 % renal
35 % renal
27 % renal
35 % renal
Substrate CYp
Yes
No
Yes
Yes
Yes
Substrate P-gp
No
Yes
Yes
Yes
Yes
Food interaction
Yes
No
No
No
No
Target
II, VII, IX, X, PC
aIIa
aXa
aXa
aXa
adverse events (thrombosis, bleeding), with the need of an immediate reverse of anticoagulation or for perioperative management, in which the control of anticoagulation is mandatory for safe surgery or invasive procedures [4, 5]. To this aim, the Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis very recently stated that monitoring is necessary in the clinical conditions previously reported. DOAC interfere with many coagulation tests and the aim is to find a test with both good linearity at increasing drug concentrations and good sensitivity for measuring therapeutic and over/sub-therapeutic levels. Many studies have been published in the past 3 years showing sensitivity and specificity of different coagulation tests for each molecule, with different reagents. Specific tests, such as diluted thrombin time (dTT), ecarin clotting time (ECT) and chromogenic ecarin test (ECA) for dabigatran and modified chromogenic anti-Xa assays for anti-Xa inhibitors, have shown the best linearity and sensitivity. DOAC anticoagulant activity should be expressed in drug concentration (ng/ml) [4]. The clinical relevance of plasma drug concentrations in relation to bleeding/thrombotic complications was underlined in the FDA report on the RE-LY study in which dabigatran trough plasma concentrations \50 ng/ml were significantly associated with the risk of stroke, while increased plasma levels were associated with increased bleeding risk. From this analysis, we can derive two considerations: (1) DOAC plasma concentration is associated with thrombotic and haemorrhagic risks; (2) the trough concentration (Ctrough) seems to be preferred to the peak concentration (Cmax) at a steady state. Finally, the measurement of the anticoagulant level is crucial for patients undergoing both elective end emergency surgery or invasive procedures, in which the simple evaluation of DOAC half-life may not be safe in the real world patient population. The RE-LY study shows that among patients undergoing elective surgery a 3.8 % rate of
123
major bleeding complications, while in emergency surgery, bleeding complications are 17.8 %. As we do for patients on vitamin K antagonists, in which the accepted cut-off for surgery/invasive procedures is a PT INR value B1.5, also for DOAC we need to know residual concentration levels and an ‘‘interventional cut-off level’’. This type of approach has been recently proposed as a consensus guideline in which dabigatran and rivaroxaban concentrations B30 ng/ml were considered the critical cut-off for allowing surgery in patients at high risk of bleeding [5]. This methodology also has great relevance to know when the normalization of DOAC anticoagulant effect is necessary, especially in case of major bleeding or emergency surgery [5]. For all these reasons, we believe that laboratory testing represents a valid mean to empower safety and efficacy of DOAC treatment. Although DOAC specific tests are not available in all clinical laboratories, in our opinion this should not be a valid reason to deny the clinical importance of anticoagulant activity measurement of these new drugs. Nevertheless, phase IV clinical trials are required to validate DOAC management. Conflict of interest
None.
References 1. Pengo V (2013) Laboratory tests during direct oral anticoagulant treatment? Yes. Intern Emerg Med 8:371–372 2. Di Minno G, Ricciardi E, Scalera A (2013) Laboratory tests during direct oral anticoagulant treatment? No. Intern Emerg Med 8:367–370 3. Gong IY, Richard BK (2013) Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol 29(7):S24– S33 4. Tripodi A, Di Iorio G, Lippi G, Testa S, Manotti C (2012) Position paper on laboratory testing for patients taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and CISMEL. Clin Chem Lab Med 12:2137–2140
Intern Emerg Med 5. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sie P (2013) Management of major bleeding complications and emergency
surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP). Ann Fr Anesth Reanim 10:691–700
123
